Few germline mutations are known to affect lung cancer risk. We performed analyses of rare variants from 39,146 individuals of European ancestry and investigated gene expression levels in 7,773 samples. We find a large-effect association with an ATM L2307F (rs56009889) mutation in adenocarcinoma for discovery (adjusted Odds Ratio = 8.82, P = 1.18 × 10-15) and replication (adjusted OR = 2.93, P = 2.22 × 10-3) that is more pronounced in females (adjusted OR = 6.81 and 3.19 and for discovery and replication). We observe an excess loss of heterozygosity in lung tumors among ATM L2307F allele carriers. L2307F is more frequent (4%) among Ashkenazi Jewish populations. We also observe an association in discovery (adjusted OR = 2.61, P = 7.98 × 10-22) and replication datasets (adjusted OR = 1.55, P = 0.06) with a loss-of-function mutation, Q4X (rs150665432) of an uncharacterized gene, KIAA0930. Our findings implicate germline genetic variants in ATM with lung cancer susceptibility and suggest KIAA0930 as a novel candidate gene for lung cancer risk.

• MeSH
• Adenocarcinoma genetics   MeSH
• Alleles MeSH
• Ataxia Telangiectasia Mutated Proteins genetics   MeSH
• White People genetics   MeSH
• Databases, Genetic MeSH
• Genetic Predisposition to Disease MeSH
• Genotyping Techniques MeSH
• Heterozygote MeSH
• Middle Aged MeSH
• Humans MeSH
• Mutation, Missense MeSH
• Lung Neoplasms genetics   MeSH
• Odds Ratio MeSH
• Risk Factors MeSH
• Pedigree MeSH
• Oligonucleotide Array Sequence Analysis MeSH
• RNA-Seq MeSH
• Aged MeSH
• Germ-Line Mutation MeSH
• Jews genetics   MeSH
• Check Tag
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Research Support, N.I.H., Extramural MeSH
• Research Support, U.S. Gov't, Non-P.H.S. MeSH